1. Field of the Invention
This invention relates to pyrimidine derivative compounds and pharmaceutically acceptable salts thereof. More specifically, this invention relates to furo2,3-d!pyrimidines, pyrrolo2,3-d!pyrimidines, pyrrolo3,2-d!pyrimidines, pyrrolo3,4-d!pyrimidines, thieno2,3-d!pyrimidines, cyclopentapyrimidines, cyclopentad!pyrimidines, pyrido2,3-d!pyrimidines and pyrido3,2-d!pyrimidines. These compounds have been found useful in resisting and treating Pneumocystis carinii and Toxoplasmosis gondii infections in immunocompromised patients, such as, for example, patients with autoimmune deficiency syndrome (AIDS). These compounds are also useful as potential antitumor, antibiotic, antimalarial, antifungal or antiprotozoal agents, or as synergistic agents when used with sulfonamides and may require the use of leucovorin rescue. These compounds are also useful as antitumor agents in cancer patients. Methods of preparing and using these compounds are also provided.
2. Description of the Background Art
Various pyrimidine systems, such as the pyrido2,3-d!pyrimidine ring system, have been studied due to their involvement in the inhibition of dihydrofolate reductase (DHFR) enzymes activity. The pyrimidine derivatives disclosed herein function as DHFR inhibitors. Because DHFR reduces dihydrofolate to tetrahydrofolate, inhibition of DHFR deprives the cell of tetrahydrofolate, without which the cell cannot produce 5,10-methylenetetrahydrofolate. 5,10-Methylene-tetrahydrofolate is essential for cell growth. The inhibition of DHFR by the compounds, and pharmaceutically acceptable salts thereof, of this invention results in the inhibition of DNA synthesis and leads to cell death. Methotrexate (MTX), trimetrexate (TMQ), piritrexim (PTX) and other folic acid analogues function as inhibitors of cell growth by similar mechanisms involving the inhibition of dihydrofolate reductase.
The pyrimidine derivatives disclosed herein also function as thymidylate synthase (TS) inhibitors. TS, along with DHFR, forms part of the systems responsible for the synthesis of deoxythymidylate (dTMP) from deoxyuridylate (dUMP). TS catalyzes the sole de novo synthesis of dTMP from dUMP. Inhibition of TS, therefore, deprives the cell of thymidine, which is an essential constituent of DNA. Typically, the compounds as described herein where X and Y are both NH.sub.2 or where X is NH.sub.2 and Y is H or CH.sub.3 and will function as DHFR inhibitors, and compounds where X is OH and Y is NH.sub.2, H, or CH.sub.3 will function as TS inhibitors, although the inventor does not wish to be bound by this generality.
Drugs useful for the reduction of cancerous cells are also known.
Elslager, Edward F., et al., "Folate Antagonists. 20. Synthesis and Antitumor and Antimalarial Properties of Trimetrexate and Related 6-(Phenylamino)methyl!-2,4-quinazolinediamines" J. Med. Chem., Vol. 26 pp. 1753-1760 (1983)), discloses the preparation of quinazolinediamines. This article states that the quinazolinediamines exhibit potent antimalarial, antibacterial and antitumor activity.
Methods of synthesizing diaminopyrido2,3-d!pyrimidines having various substituents are known. See Hurlbert, B. S., et al., "Studies on Condensed Pyrimidine Systems. XXIII. Synthesis of 2,4-Diaminopyrido2,3-d!pyrimidines from .beta.-Keto Esters", J. Med. Chem., Vol. 11, pp. 703-707 (1968), and Hurlbert, B. S., and Valenti, B. F., "Studies on Condensed Pyrimidine Systems. XXIV. The Condensation of 2,4,6-Triaminopyridimine with Malondialdehyde Derivatives", J. Med. Chem., Vol. 11, pp. 708-710 (1968).
Hurlbert, B. S., et al., "Studies on Condensed Pyrimidine Systems. XXV. 2,4-Diaminopyrido2,3-d!pyrimidines. Biological Data", J. Med. Chem., Vol. 11, pp. 711-717 (1968), discloses the antimicrobial activities of several subgroups of pyridopyrimidines. This article states that 2,4-diaminopyrido2,3-d!pyrimidines bearing alkyl and aralkyl substituents in the pyrimidine moiety are inhibitors of dihydrofolate reductase having antibacterial and antiprotozoal activity and that these compounds potentiate sulfonamides.
Grivsky, E. M., et al., "Synthesis and Antitumor Activity of 2,4-Diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido2,3-d!pyridimine", J. Med. Chem., Vol. 23, pp. 327-329 (1980), discloses the synthesis of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido2,3-dlpyridimine(BW301U ,7). This article states that BW301U,7 is as effective as methotrexate as an inhibitor of dihydrofolate reductase purified from human leukemic cells and, in contrast to metoprine, has minimal activity as an inhibitor of histamine metabolism.
Shih et al., "LY231514, a Pyrrolo2,3-d!pyrimidine-based Antifolate That Inhibits Multiple Folate-requiring Enzymes", Cancer Research, Vol. 57, pp. 1116-1123 (1997) teaches a pyrrolo 2,3-d! pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. A classical or glutamic acid substituted pyrrolo pyrimidine is disclosed.
Taylor et al., "A Dideazatetrahydrofolate Analogue Lacking a Chiral Center at C-6, N-4-2-(2-Amino-3,4-dihydro-4-oxo-7H-pyrrolo2,3-d!pyrimidin-5-yl)ethyl!b enzoyl!-L-glutamic Acid, Is an Inhibitor of Thymidylate Synthase", J. Med. Chem., Vol. 35, pp. 4450-4454 (1992) also teaches a classic pyrrolo pyrimidine compound useful in the inhibition of thymidylate synthase. Taylor reports other pyrrolo pyrimidine compounds in U.S. Pat. Nos. 4,996,206; 5,028,608; 5,248,775; 5,254,687; and 5,344,932.
Werbel, Leslie, M., et al., "Synthesis and Antimalarial Activity of a Series of 2,4-Diamino-6-(N-alkylanilino)methyl!quinazolines 1,2!", J. Heterocyclic Chem., Vol. 24, pp. 345-349 (1987), discloses the synthesis of N6 substituted quinazoline dihydrofolate reductase inhibitors. This article states that these analogs demonstrate substantial activity against Plasmodium berghei infections in mice.
Piper, J. R., et al., "Syntheses and Antifolate Activity of 5-Methyl-5-deaza Analogues of Aminopterin, Methotrexate, Folic Acid, and N.sup.10 -Methylfolic Acid", J. Med. Chem., Vol. 29, pp. 1080-1087 (1986), discloses that 5-methyl-5-deaza analogues of aminopterin and methotrexate are much more growth inhibitory than methotrexate.
Pyrido 2,3-d! and 3,2-d! pyrimidines are also disclosed in U.S. Pat. No. 5,346,900 and 5,508,281, and co-pending application Ser. Nos. 08/515,491 and 08/660,023 all of which are hereby expressly incorporated by reference.
Pyrrolo2,3-d!pyrimidines are disclosed by Gangjee et al. in "Novel 2,4-diamino-5-substituted-pyrrolo2,3-d!pyrimidines As Classical and Non-Classical Antifolate Inhibitors of Dihydrofolate Reductases", J. Med. Chem., Vol. 38, pp. 2158-2165 (Jun. 6, 1995).
Gangjee, A., et al., "Classical and Non-Classical Furo2,3-d!-Pyrimidines As Novel Antifolates: Synthesis and Biological Activities", J. Med. Chem., Vol. 37, pp. 1169-1176 (1994), discloses furo2,3-d!pyrimidines.
Mavandadi, et al., disclose 5-substituted classical and nonclassical 2,4-diaminopyrrolo2,3-d!pyrimidines as antitoxoplasma, antipneuomocystis and antitumor agents in J. Med. Chem., 40:1173-1177 (1997). Mavandadi, et al. also disclose use of pyrrolo2,3-d!pyrimidines as nonclassical inhibitors of thymidylate synthase in J. Med. Chem., 39:4563-4568 (1996).
There remains a very real and substantial need for compounds that are more active and more selective than known compounds at resisting and treating infections caused by Pneumocystis carinii and Toxoplasmosis gondii, and other organisms in immunocompromised patients, reducing the tumor size and/or the number of cancerous cells in cancer patients, and for methods of preparing and using such compounds.